Mitoquinone ameliorated airway inflammation by stabilizing β-catenin destruction complex in a steroid-insensitive asthma model

Mitochondrial dysfunction is an essential part of the pathophysiology of asthma, and potential treatments that target the malfunctioning mitochondria have attracted widespread attention. We have previously demonstrated that aberrant epithelial β-catenin signaling played a crucial role in a toluene diisocyanate (TDI)-induced steroid-insensitive asthma model. The objective of this study was to determine if the mitochondrially targeted antioxidant mitoquinone(MitoQ) regulated the activation of β-catenin in TDI-induced asthma. Mice were sensitized and challenged with TDI to generate a steroid-insensitive asthma model. Human bronchial epithelial cells (16HBE) were exposed to TDI-human serum albumin (HSA) and ethidium bromide(EB) to simulate the TDI-induced asthma model and mitochondrial dysfunction. MitoQ dramatically attenuated TDI-induced AHR, airway inflammation, airway goblet cell metaplasia, and collagen deposition and markedly protected epithelial mitochondrial functions by preserving mass and diminishing the production of reactive oxygen species (ROS). MitoQ administration stabilized β‐catenin destruction complex from disintegration and inhibited the activation of β‐catenin. Similarly, YAP1, an important constituent of β‐catenin destruction complex, was inhibited by Dasatinib, which alleviated airway inflammation and the activation of β‐catenin, and restored mitochondrial mass. In vitro, treating 16HBE cells with EB led to the activation of YAP1 and β-catenin signaling, decreased the expression of glucocorticoid receptors and up-regulated interleukin (IL)-1β, IL6 and IL-8 expression. Our results indicated that mitochondria mediates airway inflammation by regulating the stability of the β-catenin destruction complex and MitoQ might be a promising therapeutic approach to improve airway inflammation and severe asthma. The data that support the findings of this study are available from the corresponding author upon reasonable request. Some data may not be made available because of privacy or ethical restrictions. [Display omitted] •Mitoquinone reduces airway inflammation in TDI-induced steroid-resistant asthma.•Mitoquinone stabilizes β-catenin destruction complex to alleviate TDI-induced asthma.•YAP/TAZ interacts with β-catenin signaling to mediate airway inflammation.•Mitochondrial dysfunction activates YAP1 and β-catenin signaling.